1. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198
- Author
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Dennis Botman, Johanna W. Wilmink, Fonnet E. Bleeker, Tomas Radivoyevitch, Jaroslaw P. Maciejewski, Remco J. Molenaar, Cornelis M. van Drunen, W. Peter Vandertop, Cornelis J.F. Van Noorden, Myrthe A.J. Smits, Mohammed Khurshed, Jan Stap, William P.J. Leenders, Sanne A. M. van Lith, Krissie Lenting, Dionysia Dimitrakopoulou, Vashendriya V V Hira, Peter Henneman, Ron A. Hoebe, Adri Mul, Neurosurgery, CCA - Innovative therapy, Cell Biology and Histology, Graduate School, Other departments, CCA -Cancer Center Amsterdam, Human Genetics, AII - Amsterdam institute for Infection and Immunity, Ear, Nose and Throat, Other Research, Oncology, ANS - Amsterdam Neuroscience, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
Cancer Research ,Programmed cell death ,IDH1 ,Blotting, Western ,Benzeneacetamides ,Fluorescent Antibody Technique ,Antineoplastic Agents ,In Vitro Techniques ,Biology ,medicine.disease_cause ,Radiation Tolerance ,Cell Line, Tumor ,medicine ,Humans ,Gene Knock-In Techniques ,Radiosensitivity ,Enzyme Inhibitors ,Mutation ,Imidazoles ,Chemoradiotherapy ,DNA Methylation ,Isocitrate Dehydrogenase ,Oxidative Stress ,Isocitrate dehydrogenase ,Oncology ,Biochemistry ,Cell culture ,Cancer cell ,Cancer research ,Glioblastoma ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,NADP ,Oxidative stress - Abstract
Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1R132H, a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1R132H inhibitors in these patients may limit irradiation efficacy in this setting. Cancer Res; 75(22); 4790–802. ©2015 AACR.
- Published
- 2015
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